Drug discovery and development is a complex process to screen compounds based on toxicity and efficacy. Once potential drugs are identified, a series of in vitro and in vivo studies are conducted. Most in vitro studies are done using cell cultures in Petri dishes or test tubes. Following in vitro studies, in vivo studies are carried out by using animal models.
Animal models have been used extensively in drug discovery and development. However, using animal models for drug tests is expensive. In addition, animal studies often yield inaccurate and misleading results because there are differences in human and animal metabolic systems. An effective drug on animals may not be effective on humans. On the other hand, a good compound could be excluded because of the choice of an inappropriate animal species. Therefore, there is a need for a drug screening model system that is cost effective and would provide accurate prediction on a compound activity, absorption, and elimination in humans.
The inaccuracies in using an animal model to predict human responses, safety, and efficacy of a compound indicate that extrapolation from animals to humans has risks. The safety of a drug candidate is extensively studied in laboratory animals before it can be approved for clinical studies. Even though extrapolation from animal model to humans works for most patients, individual variability may cause response differences in different patients. Therefore, there is a need for a drug screening model system that minimizes the extrapolation risk from animals to humans and offers a more accurate prediction on a compound activity and toxicity at an individual patient level.
There is currently no quick, reliable way to predict whether an experimental compound will have toxic side effects on humans. One solution is the development of model systems that closely mimic the complex environment and interaction of human organ systems. In order to mimic what happens to experimental drugs in vivo, microfluidic systems lined with living cells have been developed to simulate human and animal organ systems. A known “silicon Guinea pig” device represents an attempt to mimic living organisms on a silicon microchip. With various chambers and channels simulating the organs and circulatory systems, the silicon Guinea pig has major organ functions of a live Guinea pig and can be used for drug toxicity studies. Experimental drugs can be injected into imitation blood coursing through the chambers lined with living cells. By detecting the chemical reactions happening in these chambers, it is possible to predict if the experimental drug will have a toxic effect when given to an actual human.
Following the same idea, a physiological model of a liver has been developed to study viral infection of human hepatocytes. The main component of this model is an array of micro wells that were created by deep reactive ion etching of a silicon wafer. The well array is combined with a cell-retaining filter and supported in a bioreactor housing designed to deliver a continuous perfusate across the top of the array and through the wells. A feature of the bioreactor is the distribution of cells into many tiny tissue units in the micro wells that are relatively uniformly perfused with culture medium.
Despite the need in drug development, the above microdevices are all silicon based, with micro wells and chambers for cell culturing. With these types of structures, the cells tend to line the bottom and sidewalls of the well or chamber to form two-dimensional monolayers, instead of truly 3D (three-dimensional) tissue constructs. These two-dimensional aggregates may not have normal tissue architecture to perform tissue specific functions, therefore, fail to provide an accurate model system for the tissue.
Therefore, there is a need for a model system that would provide three-dimensional tissue constructs and offer an inexpensive alternative to animal models for drug discovery and development. The present invention seeks to fulfill these needs and provides further related advantages.